Obesity has reached epidemic proportions in the United States and developing countries. While the trend of decreased physical activity and increased caloric intake is probably responsible for the recent rise in obesity, it is important to understand that these trends are playing out on a background of genetic variation in the population. Each individual's genetic background remains an important determinant of susceptibility to obesity.
The obesity epidemic is due to dietary and behavioral trends acting on a person's genetic makeup to determine body mass and susceptibility to obesity related disease. Obesity has a strong hereditary component, yet genetic pathways that contribute to obesity have not yet been elucidated. Many genetic association studies have been reported, but few have been successfully replicated, and none have led to effective treatment of common obesity.
Obesity often tracks in families. Having obese relatives increases one's risk for obesity, even if the family members do not live together or share the same patterns of exercise and food intake. Family studies and twin studies yield estimates of the fraction of the variation in the population that can be attributed to inherited variation, or the heritability (h2). Obesity is not inherited in families in a predictable pattern, but rather shows a complex pattern of segregation, indicating that multiple genes are involved. Because of this complex, multifactorial pattern, diseases and traits such as obesity are called complex genetic traits. A few studies have suggested that there are genes that act in a recessive manner and can explain a larger fraction of the variation in body mass. These results have not been consistently observed, and may also reflect the patterns seen in early onset, severe obesity caused by one or few genes, rather than the more common polygenic, later onset obesity observed in the general population. Thus, each of the obesity genes likely makes only a small contribution to body weight, but together inherited variation plays a large role in determining how an individual responds to the environmental factors of diet and physical activity.
While humans all have the same basic genetic material, every person's genome is slightly different. In comparing any two copies of the same stretch of genome, about one in every 1200 bases will be different (usually a single nucleotide polymorphism, or SNP). Most SNPs identified by comparing two chromosomes are common, and shared throughout the world—90% of such SNPs will be seen again at a frequency of at least 1%. Most of these common variants probably have no functional consequence, and are essentially the equivalent of genetic dialect, or random differences in spelling with no real significance. However, a few of these polymorphisms will alter the biologic function of a gene, either by affecting the structure of the protein or by altering the location, amount or time at which the protein is made. Some of these functional alterations will affect susceptibility to obesity and related diseases. Hence, there is a need in the art to better identify these causal variants and their interaction with each other and environmental factors.
Accordingly, there exists a need in the art for methods of early detection and identification of high-risk individuals who are susceptible to developing abnormal body weight. There is also a need for compositions and methods that can modulate metabolism and/or treat obesity.